Rhodium(III)-Catalyzed Synthesis of Aryl Spirocycles by Aromatic C-H Activation/Intramolecular Heck-Type Reaction

Article abstract of DOI:10.1002/adsc.201500768

The rhodium(III)-catalyzed aromatic C-H activation/intramolecular Heck-type reaction has been studied to synthesize spirocyclic compounds, an important class of molecules in medicinal chemistry and natural product synthesis. This approach was efficient with a variety of substituted N-methoxybenzamides tethered to different cyclic alkenes having a 5-, 6- or 7-membered ring. This practical method affords sterically hindered o-substituted aryl spirocycles that are valuable compounds for further functionalization to access relevant building blocks.

Full text of DOI:10.1002/adsc.201500768

COMMUNICATIONS
DOI: 10.1002/adsc.201500768
Rhodium(III)-Catalyzed Synthesis of Aryl Spirocycles by
À
Aromatic C H Activation/Intramolecular Heck-Type Reaction
Laurent Chabaud,a,* Quentin Raynal,a Elvina Barre,a and Catherine Guilloua,*
a
Institut de Chimie des Substances Naturelles, 1, Avenue de la terrasse, CNRS UPR 2301, UniversitØ Paris-Sud, 91198
Gif-sur-Yvette, France
Fax: (+33)-1-6907-7247(0); phone: (+33)-1-6982-3075; e-mail: laurent.chabaud@cnrs.fr or catherine.guillou@cnrs.fr
Received: August 16, 2015; Revised: September 15, 2015; Published online: November 25, 2015
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500768.
À
Abstract: The rhodium(III)-catalyzed aromatic C
H activation/intramolecular Heck-type reaction has
been studied to synthesize spirocyclic compounds,
an important class of molecules in medicinal
chemistry and natural product synthesis. This ap-
proach was efficient with a variety of substituted N-
methoxybenzamides tethered to different cyclic al-
kenes having a 5-, 6- or 7-membered ring. This
practical method affords sterically hindered o-sub-
stituted aryl spirocycles that are valuable com-
pounds for further functionalization to access rele-
vant building blocks.
À
Keywords: catalysis; C H activation; Heck-type re-
action; rhodium; spiro compounds
Scheme 1. Intramolecular Heck spirocyclization catalyzed by
Pd(0) vs. Rh(III).
The spirocyclic scaffold is a unique structural feature
commonly embedded in various natural products and
synthetic congeners that possess a wide spectrum of H) activation reaction directed by a neighbouring
biological properties.[1] Spiro-linked heterocycles have group has received tremendous interest.[4,5] Because
been incorporated in numerous classes of pharma- of its high efficiency, functional-group tolerance and
ceutically active molecules and are considered by me- selectivity, rhodium(III) catalysis has emerged, over
À
À
Recently, the metal-catalyzed aromatic C H (ArC
À
dicinal chemists as “privileged structures” in drug dis- the last few years, as a powerful tool in ArC H acti-
covery.[2] The importance of spirocycles has also been vation.[5] Among the numerous transformations cata-
illustrated by their use as valuable synthetic inter- lyzed by Rh(III), the oxidative Heck-type olefination
mediates in the total synthesis of natural products. has been extensively studied. This has resulted in the
Despite the utility of spirocyclic compounds, the effi- development of several intermolecular reactions di-
cient formation of the spiranic quaternary carbon is rected by different functional groups such as amides,[6]
[8]
protected anilines,[7] ketones,[7] ArCONH OMe,
À
still an important challenge in organic synthesis.
Intramolecular Heck arylation reactions catalyzed ArNR2 O, etc. Recently, it has been showed that
by Pd(0) are useful methods to build spirocycles 2 benzamides (ArCONH R) are able to direct the rho-
embedding an aryl moiety [Scheme 1, Eq. (1)], which dium(III)-catalyzed intramolecular reaction with
have been used in several total syntheses of natural a tethered olefin. Depending on the nature of the
products.[3] However, in this approach the introduc- amide, a hydroarylation (R=Me), amidoarylation
tion of the halogen atom can be a long and tedious (R=OPiv) or Heck-type reaction (R=OMe) can be
process, especially for substrates bearing an ortho- performed.[10] However, the studies has been limited
[9]
À
À
substituent (1, R¼ H).
to the synthesis of functionalized fused heterocycles.
3880
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2015, 357, 3880 – 3884

COMMUNICATIONS
Rhodium(III)-Catalyzed Synthesis of Aryl Spirocycles
Our interest in the synthesis of aryl spirocyclic com-
The optimized conditions of the Rh(III)-catalyzed
pounds,[4a,d] led us to investigate the Rh(III)-catalyzed Heck-type spirocyclization were then applied to a vari-
Heck-type spirocyclization of aryl alkenes
[Scheme 1, Eq. (2)].[11]
3
ety of substituted benzamides tethered to a cyclic
alkene by different linkers (Table 2). We observed in
We describe herein the successful development of most cases that the substitution of the aryl moiety de-
a practical, regioselective and efficient synthesis of creased the reaction rate. Thus, unless otherwise men-
highly hindered o-substituted spirocycle 4 from easily tioned, we carried out all the reactions at 608C over-
accessible cyclic alkene 3. Moreover, we demonstrate night. Gratifyingly, we found that the substitution on
that compound 4 can be used as a platform to access the aryl moiety was well tolerated to afford [6,5,6]-
a variety of densely functionalized spirocycles.
spirocycles (entries 1–6). For instance, the ortho-
Investigations were first carried out by selecting fluoro-substituted benzamide 6a cyclized into the tri-
alkene benzamide 5a and subjecting it to a catalytic cyclic compound 6b in 88% (entry 1). Other sub-
amount of [RhCp*Cl2]2 with 2 equivalents of CsOAc strates 7a and 8a bearing an ortho electron-withdraw-
in methanol (c=0.2M) at room temperature ing (NO2, entry 2) or electron-donating (OMe,
(Table 1). Under these initial conditions, we observed entry 3) group respectively reacted well to provide 7b
a clean reaction, which afforded exclusively the de- and 8b in good yields.
sired spirocycle 5b isolated in 71% yield after 12 h
Electron-rich benzamides 9a bearing a dioxolane
(entry 1). This result contrasts with the recent report (entry 4), and 10a tethered to two cyclic alkenes
from Rovis et al. that showed on one example that (entry 5) gave products 9b and 10b in 70% and 83%
the benzoate-directed Heck-type reaction with a teth- yields, respectively. The steric hindrance around the
ered cyclohexene performs in moderate yield (54%) amide moiety (i.e., 11a, entry 6) did not affect the re-
and also gave 20% of impurity.[10c] Increasing the tem- activity, since 11b was isolated in 76% yield. In con-
perature to 608C significantly decreases the reaction trast, cyclization of the sterically demanding cyclohex-
time to 2 h to afford 5b still in good isolated chemical ene 12a derived from myrtenol, took place at 1008C
yield (entry 2). The use of a silver additive (AgSbF6 over 3 days to afford the spirocycle 12b in 60% yield
20 mol%, entry 3) or other rhodium catalyst (69% brsm, entry 7).
{[Cp*Rh(CH3CN)3][SbF6]2, entry 4} did not have a sig-
We next investigated the effect of the ring size of
nificant influence on the yield. Among the different the cyclic alkene with substrates 13a and 14a (en-
solvents tested (t-AmOH, 1,2-DCE or CH3CN, en- tries 8 and 9). Under the optimal reaction conditions
tries 5–7), we found that tert-amyl alcohol provided they afforded the corresponding [6,5,5]- and [6,5,7]-
the spirocycle 5b with the highest isolated yield (86%, spirocycles 13b and 14b, respectively, in good yields.
entry 5).
Furthermore the [6,6,6]-tricyclic compound 15b could
be obtained with a 73% yield by cyclization of 15a
(entry 10).
Substrates bearing a different linker between the
Table 1. Optimization of the Rh(III)-catalyzed Heck-type benzamide and the cyclic alkene were then examined.
spirocyclization of 5a.
For instance, the indole derivative 16a was subjected
to the optimal catalytic system at 808C. With this sub-
strate, the cyclization was found to be sluggish, and
only 50% of the starting material was consumed after
3 days (entry 11). However, we were able to isolate
the desired product 16b in 23% yield as well as 10%
of the cyclized NHOMe amide 16c (R=OMe). This
result indicates that the rhodium(I) species generated
after the reaction is not efficiently reoxidized into
Rh(III). Gratifyingly, the use of Cu(OAc)2 (2.1 equiv.)
as an external oxidant in combination with AgSbF6
(10 mol%) afforded the indole derivative 16b in an
improved 57% yield (entry 12).[12]
Spirobenzofuran-2-one and spirooxindole units are
important structural motifs found in natural and un-
natural compounds with diverse and important bio-
logical activities.[13] We showed that using this meth-
odology we were able to cyclize the ester linked ben-
zamide 17a, to give spirobenzofuran-2-one 17b in
77% yield (entry 13). Furthermore, the reaction per-
En-
try
Catalyst
(mol%)
Solvent
T
[8C]
t
Yield
[%][a]
[h]
1
[RhCp*Cl2]2 (2.5)
[RhCp*Cl2]2 (2.5)
[RhCp*Cl2]2 (2.5)
[Cp*Rh(MeCN)3]
[SbF6]2 (5)
MeOH
MeOH
MeOH
MeOH
25
60
60
60
12
2
2
71
73
71
73
2
3[b]
4
2
5
6
7
[RhCp*Cl2]2 (2.5)
[RhCp*Cl2]2 (2.5)
[RhCp*Cl2]2 (2.5)
t-AmOH
1,2-DCE
MeCN
60
60
60
2
2
2
86
28[c]
71
[a]
Isolated yield.
10 mol% of AgSbF6 was used.
Conversion estimated by H NMR on the crude mixture.
[b]
[c]
1
Adv. Synth. Catal. 2015, 357, 3880 – 3884
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3881

COMMUNICATIONS
Laurent Chabaud et al.
Table 2. Rh(III)-catalyzed Heck-type spirocyclization of benzamides 6a–18a.
[a]
Isolated yield.
[b]
Reaction carried out at 1008C for 3 days, Yield brsm 69%.
[RhCp*Cl2]2 (5 mol%), Cu(OAc)2 (2.1 equiv.) and AgSbF6 (10 mol%) were used.
5 mol% of [RhCp*Cl2]2 were used.
[c]
[d]
3882
asc.wiley-vch.de
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2015, 357, 3880 – 3884

COMMUNICATIONS
Rhodium(III)-Catalyzed Synthesis of Aryl Spirocycles
converted into diversely substituted spiro-linked het-
erocycles that could be of interest in medicinal
chemistry or in the total synthesis of natural products.
Experimental Section
General Procedure; Ether Synthesis by Mitsunobu
Reaction
To a solution of phenol (1 equiv.), allylic alcohol (1 equiv.),
triphenylphosphine (1.4 equiv.) in THF (5 mLmmolÀ1) was
added diethyl azodicarboxylate (1.4 equiv.) at 08C. The reac-
tion mixture was stirred overnight at room temperature.
Then the reaction mixture was diluted with EtOAc and the
organic layer was washed with water followed by brine. The
organic layer was washed with brine and dried over Na2SO4.
The solvent was removed under vacuum and the crude mix-
ture purified through silica gel to afford the corresponding
ether.
General Procedure; Acid Synthesis
To a solution of ester (1 equiv.) in ethanol (5.9 mLmmolÀ1)
was added a 3M solution of NaOH (3.5 mLmmolÀ1) at
room temperature. The mixture was stirred for 2 h, then
HCl (2N) was added at 08C until pH 2–3. The aqueous
layer was extracted with EtOAc and the solvent was evapo-
rated under vacuum. The crude mixture was used without
purification.
Scheme 2. Examples of the functionalization of spirocyclic
compounds 5b and 18b.
forms well with the amide 18a to give the spirooxin-
dole building block 18b in 60% yield (entry 14).
Having established the efficiency of the Rh(III)-
catalyzed spirocyclization of benzamides 5a–18a, we
next explored some functionalizations (Scheme 2).
We showed that from a single compound, a variety of
o-substituted spirocycles could be obtained. For in-
stance, epoxidation of the olefin of 5b, using mCPBA,
selectively afforded 19 in 68% yield. Manganese-cata-
lyzed allylic oxidation of alkene 5b gave the a,b-unsa-
General Procedure; Amide Synthesis
The corresponding carboxylic acid (1 equiv.) was dissolved
in dichloromethane (5 mLmmolÀ1) and oxalyl chloride
(1.2 equiv) was added. One drop of DMF was added and
the solution was stirred at room temperature for 30 min.
The mixture was concentrated by rotavap. Ethyl acetate
(2.7 mLmmolÀ1), O-methylhydroxylamine hydrochloride
(1.1 equiv.), potassium carbonate (2.4 equiv), and water
turated ketone 20 in 54% yield (72% brsm). The (1.3 mLmmolÀ1) were added in succession, and the suspen-
sion was stirred for five hours. The aqueous layer was sepa-
rated and extracted once with ethyl acetate. The organic
layers were combined, washed with brine, and dried over
Na2SO4. The solution was filtered and concentrated under
reduced pressure. The solvent was removed under vacuum
and the crude mixture purified through silica gel to afford
the corresponding amide.
same reaction performed on the spirooxindole 18b
led to the enone 21 in 66% yield.
The utility of the primary benzamide resulting from
the cyclization was next illustrated. Its efficient trans-
formation into a nitrile group was achieved by using
oxalyl chloride (i.e., 22, 90%). Furthermore, hyperva-
lent iodine-mediated Hofmann rearrangement in
methanol afforded methyl carbamate 23 in 77% yield.
In turn, hydrolysis of compound 23 furnished quanti-
tatively the spirocyclic aniline 24.
General Procedure; Rhodium(III)-Catalyzed Heck-
Type Reaction
In summary, we have developed a practical and
straightforward synthesis of sterically hindered ortho-
substituted aryl spirocycles using a Rh(III)-catalyzed
ArCH activation/intramolecular Heck-type reaction.
This approach is tolerant with electron withdrawing
and donating groups on the aromatic ring, and allows
the synthesis of [6,5,6], [6,5,5], [6,5,7], and [6,6,6] aryl
A sealed tube was charged with a stir bar, amide (1 equiv.),
[RhCp*Cl2]2 (0.025 equiv.) and CsOAc (2 equiv.). The tube
was purged three times by vacuum and argon, then MeOH
(0.2M) was added. The vial was sealed and the mixture
stirred at the indicated temperature for the indicated time.
The reaction mixture was concentrated under vacuum. The
crude residue was purified by column chromatography on
spirocyclic systems. Some of these compounds were silica gel to afford the corresponding spirocycle.
Adv. Synth. Catal. 2015, 357, 3880 – 3884
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3883

COMMUNICATIONS
Laurent Chabaud et al.
pp 303–308; c) G. Song, F. Wang, X. Li, Chem. Soc.
Rev. 2012, 41, 3651–3678; d) F. Zhang, D. R. Spring,
Chem. Soc. Rev. 2014, 43, 6906–6919; e) N. Kuhl, N.
Schroder, F. Glorius, Adv. Synth. Catal. 2014, 356,
1443–1460; f) X.-S. Zhang, K. Chen, Z.-J. Shi, Chem.
Sci. 2014, 5, 2146–2159; g) J. Mo, L. Wang, Y. Liu, X,
Cui, Synthesis 2015, 47, 439–459.
Acknowledgements
This work was supported by CNRS and ICSN.
References
[6] F. W. Patureau, T. Besset, F. Glorius, Angew. Chem.
2011, 123, 1096–1099; Angew. Chem. Int. Ed. 2011, 50,
1064–1067.
[7] F. W. Patureau, F. Glorius, J. Am. Chem. Soc. 2010, 132,
9982–9983.
[1] a) R. Rios, Chem. Soc. Rev. 2012, 41, 1060–1074; b) S.
Kotha, A. Deb, K. Lahiri, E. Manivannan, Synthesis
2009, 165–193; c) V. A. D’yakonov, O. A. Trapeznikova,
A. de Meijere, U. M. Dzhemilev, Chem. Rev. 2014, 114,
5775–5814.
[8] For selected leading references see: a) S. Rakshit, C.
Grohmann, T. Besset, F. Glorius, J. Am. Chem. Soc.
2011, 133, 2350–2353; b) N. Guimond, S. I. Gorelsky, K.
Fagnou, J. Am. Chem. Soc. 2011, 133, 6449–6457.
[9] X. Huang, J. Huang, C. Du, X. Zhang, F. Song, J. You,
Angew. Chem. 2013, 125, 13208–13212; Angew. Chem.
Int. Ed. 2013, 52, 12970–12974.
[10] a) T. A. Davis, T. K. Hyster, T. Rovis, Angew. Chem.
2013, 125, 14431–14435; Angew. Chem. Int. Ed. 2013,
52, 14181–14185; b) Z. Shi, M. Boultadakis-Arapinis,
D. C. Koester, F. Glorius, Chem. Commun. 2014, 50,
2650–2652; c) T. Davis, C. Wang, T. Rovis, Synlett 2015,
26, 1520–1524; d) B. Ye, P. A. Donets, N. Cramer,
Angew. Chem. 2014, 126, 517–521; Angew. Chem. Int.
Ed. 2014, 53, 507–511.
[11] For a recent report on iridium(III)-catalyzed synthesis
of spiro compounds see: T. Zhou, L. Li, B. Li, H. Song,
B. Wang, Org. Lett. 2015, 17, 4204–4207.
[12] The uncyclized indole derivative bearing a primary
amide was also isolated in 25% yield. See the Support-
ing Information.
[13] a) B. Yu, D.-Q. Yu, H.-M. Liu, Eur. J. Med. Chem.
2015, 97, 673–698; b) D. Cheng, Y. Ishihara, B. Tan,
C. F. Barbas, ACS Catal. 2014, 4, 743–762; c) L. Hong,
R. Wang, Adv. Synth. Catal. 2013, 355, 1023–1052;
d) N. R. Ball-Jones, J. J. Badillo, A. K. Franz, Org.
Biomol. Chem. 2012, 10, 5165–5181; e) Z.-Y. Jiang, J.
Zhou, C.-G. Huang, Q.-F. Hu, X.-Z. Huang, W. Wang,
L.-Z. Zhang, G.-P. Li, F.-T. Xia, Tetrahedron 2015, 71,
3844–3849; f) S. Wada, T. Hitomi, H. Tokuda, R.
Tanaka, Chem. Biodiversity 2010, 7, 2303–2308;
g) M. W. Pertino, C. Theoduloz, J. A. Rodríguez, T.
YµÇez, V. Lazo, G. Schmeda-Hirschmann, J. Nat. Prod.
2010, 73, 639–643.
[2] a) Y. Zheng, C. M. Tice, S. B. Singh, Bioorg. Med.
Chem. Lett. 2014, 24, 3673–3682; b) M. E. Welsch, S. A.
Snyder, B. R. Stockwell, Curr. Opin. Chem. Biol. 2010,
14, 347–361.
[3] For selected examples, see: a) C. Guillou, J.-L. Beu-
nard, E. Gras, C. Thal, Angew. Chem. 2001, 113, 4881–
4882; Angew. Chem. Int. Ed. 2001, 40, 4745–4746; b) C.
Bru, C. Thal, C. Guillou, Org. Lett. 2003, 5, 1845–1846;
c) J. Pereira, M. Barlier, C. Guillou, Org. Lett. 2007, 9,
3101–3103; d) M. Varin, E. BarrØ, B. Iorga, C. Guillou,
Chem. Eur. J. 2008, 14, 6606–6608; e) P.-H. Liang, J.-P.
Liu, L.-W. Hsin, C.-Y. Cheng, Tetrahedron 2004, 60,
11655–11660; f) W. G. Earley, J. E. Jacobsen, A. Madin,
G. P. Meier, C. J. OꢁDonnell, T. Oh, D. W. Old, L. E.
Overman, M. J. Sharp, J. Am. Chem. Soc. 2005, 127,
18046–18053; g) S. Grecian, J. AubØ, Org. Lett. 2007, 9,
3153–3156; h) P. Liu, J. H. Seo, S. M. Weinreb, Angew.
Chem. 2010, 122, 2044–2047; Angew. Chem. Int. Ed.
2010, 49, 2000–2003; i) T. Honda, H. Arai, N. Yamamo-
to, K. Takahashi, Heterocycles 2012, 84, 327–331.
[4] For selected reviews: a) X. Chen, K. M. Engle, D.-H.
Wang, J.-Q. Yu, Angew. Chem. 2009, 121, 5196–5217;
Angew. Chem. Int. Ed. 2009, 48, 5094–5115; b) J.
Wencel-Delord, F. Glorius, Nat. Chem. 2013, 5, 369–
375; c) L. Yang, H. Huang, Chem. Rev. 2015, 115,
3468–3517; d) S. I. Kozhushkov, L. Ackermann, Chem.
Sci. 2013, 4, 886–896; e) G. Yan, X. Wu, M. Yang, Org.
Biomol. Chem. 2013, 11, 5558–5578; f) Y. Segawa, T.
Maekawa, K. Itami, Angew. Chem. Int. Ed. 2015, 54,
66–81.
[5] For recent reviews on Rh(III) catalysis: a) T. Satoh, M.
Miura, Chem. Eur. J. 2010, 16, 11212–11222; b) K. M.
Oberg, T. Rovis, in: Asymmetric Synthesis II, (Eds.: M.
Christmann, S. Bräse), Wiley-VCH, Weinheim, 2012,
3884
asc.wiley-vch.de
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2015, 357, 3880 – 3884